Sorafenib (D3)
(Synonyms: 索拉非尼-D3,Bay 43-9006-d3; Donafenib) 目录号 : GC37664
An internal standard for the quantification of sorafenib
Cas No.:1130115-44-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Sorafenib-d3 is intended for use as an internal standard for the quantification of sorafenib by GC- or LC-MS. Sorafenib is a multi-kinase inhibitor that inhibits Raf-1 and B-RAF (IC50s = 6 and 22 ?M, respectively), as well as the receptor tyrosine kinases VEGFR2, VEGFR3, PDGFRβ, FLT3, and c-Kit (IC50s = 90, 15, 20, 57, and 58 nM, respectively).1,2 It is selective for these kinases over 12 other kinases, including ERK1, MEK1, EGFR, and HER2 (IC50s = >10 ?M for all).2 Sorafenib inhibits proliferation of PLC/PRF/5 and HepG2 cells (IC50s = 6.3 and 4.5 ?M, respectively) and induces apoptosis in these cells.3 It completely inhibits tumor growth in a PLC/PRF/5 mouse xenograft model when administered at a dose of 30 mg/kg and reduces basic FGF-induced angiogenesis in a Matrigel? assay in vivo.3,4 Sorafenib (10 ?M) induces ferroptotic cell death in HT-1080 fibrosarcoma cells, an effect that can be blocked by the ferroptosis inhibitors ferrostatin-1 , deferoxamine , and β-mercaptoethanol.5 It inhibits glutamate release by the system xc- cystine/glutamate transporter in HT-1080 cells when used at concentrations ranging from 2.5 to 10 ?M, decreases glutathione levels, and increases lipid peroxidation. Sorafenib also inhibits replication of hepatitis C virus (HCV) in Huh7.5 cells (IC50 = 7.2 ?M).6 Formulations containing sorafenib have been used in the treatment of hepatocellular, renal cell, and thyroid carcinomas.
1.Lyons, J.F., Wilhelm, S., Hibner, B., et al.Discovery of a novel Raf kinase inhibitorEndocr. Relat. Cancer8(3)219-225(2001) 2.Wilhelm, S.M., Carter, C., and Tang, L.BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesisCancer Res.64(19)7099-7109(2004) 3.Liu, L., Cao, Y., Chen, C., et al.Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5Cancer Res.66(24)11851-11858(2006) 4.Murphy, D.A., Makonnen, S., Lassoued, W., et al.Inhibition of tumor endothelial ERK activation, angiogenesis, and tumor growth by sorafenib (BAY43-9006)Am. J. Pathol.169(5)1875-1885(2006) 5.Dixon, S.J., Patel, D.N., Welsch, M., et al.Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosisElife3e02523(2014) 6.Himmelsbach, K., Sauter, D., Baumert, T.F., et al.New aspects of an anti-tumour drug: Sorafenib efficiently inhibits HCV replicationGut58(12)1644-1653(2009)
| Cas No. | 1130115-44-4 | SDF | |
| 别名 | 索拉非尼-D3,Bay 43-9006-d3; Donafenib | ||
| Canonical SMILES | O=C(C1=NC=CC(OC2=CC=C(NC(NC3=CC=C(Cl)C(C(F)(F)F)=C3)=O)C=C2)=C1)NC([2H])([2H])[2H] | ||
| 分子式 | C21H13D3ClF3N4O3 | 分子量 | 467.84 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1375 mL | 10.6874 mL | 21.3748 mL |
| 5 mM | 0.4275 mL | 2.1375 mL | 4.275 mL |
| 10 mM | 0.2137 mL | 1.0687 mL | 2.1375 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
A sorafenib-sparing effect in the treatment of thyroid carcinoma cells attained by co-treatment with a novel isoflavone derivative and 1,25 dihydroxyvitamin D3
J Steroid Biochem Mol Biol 2018 Sep;182:81-86.PMID:29702263DOI:10.1016/j.jsbmb.2018.04.013.
Background: Sorafenib improves progression-free survival in patients with progressive radioactive iodine-refractory differentiated thyroid carcinoma, but causes severe side effects. Estrogens may accelerate thyroid carcinoma cell growth. Our group recently reported that isoflavone derivative 7-(O)-carboxymethyl daidzein conjugated to N-t-boc-hexylenediamine (cD-tboc), a novel anti-estrogenic compound, retards the growth of both thyroid carcinoma cell lines and cultured human carcinoma cells. Vitamin D receptor (VDR) is expressed in malignant cells and responds to 1,25 dihydroxyvitamin D3 (1.25D) by decreased proliferative activity in vitro. The purpose of this study was to examine the effects of vitamin D metabolites (VDM) on the expression of estrogen receptors (ERs), VDR, and 1OHase mRNA, and to evaluate the inhibitory effect of low doses of Sorafenib in combination with cDtboc and VDM on cell proliferation in cultured human papillary thyroid carcinoma (PTC). Methods: In 19 cultured PTC specimens and 19 normal thyroid specimens, harvested during thyroidectomies from the same patients, expression levels of ERα, ERβ, VDR, and 1 alpha-hydroxylase (1OHase) mRNA (by quantitative real-time PCR) were determined at baseline and after treatment with VMD. Cell proliferation was determined by measurement of 3[H] thymidine incorporation after treatment with Sorafenib alone, Sorafenib with added 1.25D or cD-tboc, and Sorafenib with both 1.25D and cD-tboc added. Results: 1,25D increased mRNA expression of all tested genes in the malignant and normal thyroid cells, while the ERα mRNA of the normal cells was unaffected. 1.25D dose-dependently inhibited cell proliferation in the malignant cells. The inhibitory effect of Sorafenib on cell proliferation in the malignant cells was amplified after the addition of cDtboc and 1.25D, such that the maximal inhibition was not only greater, but also had been attained at a 10-fold lower concentration of Sorafenib (20 μg/ml). This inhibition was similar to that of the generally used concentration of Sorafenib (200 μg/ml) alone. Conclusions: The demonstration that low concentrations of cDtboc and 1.25D markedly amplify the inhibitory effect of Sorafenib on the growth of human PTC supports the use of a 10-fold lower concentration of Sorafenib. The findings may promote a new combination treatment for progressive radioactive iodine-refractory PTC.
Sorafenib in Patients with Hepatocellular Carcinoma-Results of the Observational INSIGHT Study
Clin Cancer Res 2017 Oct 1;23(19):5720-5728.PMID:28698202DOI:10.1158/1078-0432.CCR-16-0919.
Purpose: Sorafenib is the only currently approved systemic therapy for advanced hepatocellular carcinoma (HCC). We aimed to evaluate the safety and efficacy of Sorafenib therapy in patients with HCC under real-life conditions regarding patient, tumor characteristics, and any adverse events at study entry and at follow-up visits every 2 to 4 months.Experimental Design: The current INSIGHT study is a noninterventional, prospective, multicenter, observational study performed in 124 sites across Austria and Germany between 2008 and 2014.Results: Median overall survival and time to progression (RECIST) were found to be dependent on baseline Barcelona Clinic Liver Cancer (BCLC) tumor stage (A: 29.2, B: 19.6, C: 13.6, D: 3.1 and A: 6.0, B: 5.5, C: 3.9, and D: 1.7 months, respectively), Child-Pugh liver function (A: 17.6, B: 8.1, C: 5.6 and A: 5.3, B: 3.3, C: 2.5 months, respectively), and performance status of the patient; however, age did not affect prognosis. Sorafenib-related adverse events at any grade occurred in 64.9% of patients, with diarrhea (35.4%), hand-foot-skin reaction (16.6%), nausea (10.3%), and fatigue (11.2%) occurring most frequently.Conclusions: Sorafenib treatment was shown to be effective in a real-life setting, in agreement with previously reported clinical trial data. The therapy was found to have an acceptable safety profile, with predominantly mild to moderate side effects. Clin Cancer Res; 23(19); 5720-8. ©2017 AACR.
Sorafenib inhibits endogenous and IL-6/S1P induced JAK2-STAT3 signaling in human neuroblastoma, associated with growth suppression and apoptosis
Cancer Biol Ther 2012 May;13(7):534-41.PMID:22406995DOI:10.4161/cbt.19603.
Neuroblastoma is the most common extracranial solid tumor in the pediatric population. Sorafenib (Nexavar), a multikinase inhibitor, blocks cell proliferation and induces apoptosis in certain types of cancers. Here, we tested antitumor effects of Sorafenib (≤ 10 µM) on four human neuroblastoma cell lines, CHLA255, CHLA171, CHLA90 and SK-N-AS. Sorafenib inhibited cell proliferation and induced apoptosis of neuroblastoma tumor cells in a dose-dependent manner. Sorafenib inhibited phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) proteins at Tyr705 in these cells, associated with inhibition of phosphorylated JAK2, an upstream kinase that mediates STAT3 phosphorylation. Expression of a constitutively-activated STAT3 mutant (pSTAT3-C) partially blocked the antitumor effects of Sorafenib on neuroblastoma cells. Sorafenib also inhibited the phosphorylation of STAT3 induced by IL-6 and sphingosine-1-phosphate (S1P), a recently identified regulator for STAT3, in these tumor cells. Moreover, Sorafenib downregulated phosphorylation of MAPK (p44/42) in neuroblastoma cells, consistent with inhibition of their upstream regulators MEK1/2. Sorafenib inhibited expression of cyclin E, cyclin D1/D2/D3, key regulators for cell cycle, and the antiapoptotic proteins Mcl-1 and survivin. Finally, Sorafenib suppressed the growth of human neuroblastoma cells in a mouse xenograft model. Taken together, these findings suggest the potential use of Sorafenib for the treatment of pediatric neuroblastomas.
Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas
Mol Cancer Ther 2008 Nov;7(11):3519-26.PMID:19001435DOI:10.1158/1535-7163.MCT-08-0138.
Medulloblastomas are the most frequent malignant brain tumors in children. Sorafenib (Nexavar, BAY43-9006), a multikinase inhibitor, blocks cell proliferation and induces apoptosis in a variety of tumor cells. Sorafenib inhibited proliferation and induced apoptosis in two established cell lines (Daoy and D283) and a primary culture (VC312) of human medulloblastomas. In addition, Sorafenib inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) in both cell lines and primary tumor cells. The inhibition of phosphorylated STAT3 (Tyr(705)) occurs in a dose- and time-dependent manner. In contrast, AKT (protein kinase B) was only decreased in D283 and VC312 medulloblastoma cells and mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2) were not inhibited by Sorafenib in these cells. Both D-type cyclins (D1, D2, and D3) and E-type cyclin were down-regulated by Sorafenib. Also, expression of the antiapoptotic protein Mcl-1, a member of the Bcl-2 family, was decreased and correlated with apoptosis induced by Sorafenib. Finally, Sorafenib suppressed the growth of human medulloblastoma cells in a mouse xenograft model. Together, our data show that Sorafenib blocks STAT3 signaling as well as expression of cell cycle and apoptosis regulatory proteins, associated with inhibition of cell proliferation and induction of apoptosis in medulloblastomas. These findings provide a rationale for treatment of pediatric medulloblastomas with Sorafenib.
Coadministration of Sorafenib with rottlerin potently inhibits cell proliferation and migration in human malignant glioma cells
J Pharmacol Exp Ther 2006 Dec;319(3):1070-80.PMID:16959960DOI:10.1124/jpet.106.108621.
Mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) are activated in the majority of gliomas and contribute to tumor cell growth and survival. Sorafenib (Bay43-9006; Nexavar) is a dual-action Raf and vascular endothelial growth factor receptor inhibitor that blocks receptor phosphorylation and MAPK-mediated signaling and inhibits growth in a number of tumor types. Because our initial studies of this agent in a series of glioma cell lines showed only partial growth inhibition at clinically achievable concentrations, we questioned whether inhibition of PKC signaling using the PKC-delta inhibitor rottlerin might potentiate therapeutic efficacy. Proliferation assays, apoptosis induction studies, and Western immunoblot analysis were conducted in cells treated with Sorafenib and rottlerin as single agents or in combination. Sorafenib and rottlerin reduced proliferation in all cell lines when used as single agents, and the combination produced marked potentiation of growth inhibition. Flow-cytometric measurements of cells stained with Annexin V-propidium iodide and immunocytochemical assessment of cytochrome c and apoptosis-inducing factor release demonstrated that addition of rottlerin resulted in significantly higher levels of apoptosis than Sorafenib alone. In addition, the combination of Sorafenib and rottlerin reduced or completely inhibited the phosphorylation of extracellular signal-regulated kinase and Akt and down-regulated cell cycle regulatory proteins such as cyclin-D1, cyclin-D3, cyclin-dependent kinase (cdk)4, and cdk6 in a dose- and time-dependent manner. Our results clearly indicate that inhibition of PKC-delta signaling enhances the antiproliferative effect of Sorafenib in malignant human glioma cell lines and support the examination of combinations of signaling inhibitors in these tumors.